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study intervention was approved by the FDA
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The purpose of the study is to investigate if intravenous fish oil, commercially available as Omegaven, safely and effectively reverses parenteral nutrition associated cholestasis in children.
Infants dependent on parenteral nutrition for greater than 1 year who develop parenteral nutrition associated cholestasis will universally face mortality unless they receive a timely liver and/or small bowel transplant. Although transplant survival has improved in recent years, survival is not guaranteed, and transplant care remains costly. Alternative nutritional and pharmacological strategies are imperative to improve the clinical outcomes of infants with intestinal failure and parenteral nutrition associated cholestasis. In both animal and human studies, intravenous fish oil, a lipid emulsion rich in omega-3 fatty acids and Vitamin E, and lacking phytosterols, has been shown to ameliorate parenteral nutrition associated cholestasis and improve morbidity and mortality. The purpose of this pilot study is to investigate if Omegaven, a commercially available intravenous fish oil, at 1 g/kg/d, will safely reverse liver disease in 80 subjects with parenteral nutrition associated cholestasis. Subjects can initially receive a maximum of 6 months (24 weeks) of intravenous fish oil. If the subject re-develops liver disease and still satisfies inclusion/exclusion criteria, the intervention can be restarted. Study subjects will be compared to a historical cohort of children with Short Bowel Syndrome and parenteral nutrition associated cholestasis who have been receiving standard intravenous soybean oil for > 60 days. The fish oil cohort will be followed for a total of 5 years to determine if transplant-free mortality is reduced.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Omegaven | Experimental | 0.5 g/kg/d IV x 2 days, then 1 g/kg/d IV for 24 weeks or until parenteral nutrition discontinuation, death or transplant, whichever comes first. Subjects are eligible to restart Omegaven should they re-satisfy inclusion/exclusion criteria. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Omegaven | Drug | 0.5 g/kg/d intravenous every day for 2 days, then 1 g/kg/d intravenous everyday |
|
| Measure | Description | Time Frame |
|---|---|---|
| Time to Reversal of Parenteral Nutrition Associated Cholestasis | weeks | 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) |
| Measure | Description | Time Frame |
|---|---|---|
| Death | expiration | 24 weeks, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) |
| Number of Participants Who Underwent a Transplant | includes isolated liver or multi-visceral transplant including liver graft |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Kara L Calkins, MD | University of California, Los Angeles | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California, Los Angeles | Los Angeles | California | 90095 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23894176 | Result | Calkins KL, Dunn JC, Shew SB, Reyen L, Farmer DG, Devaskar SU, Venick RS. Pediatric intestinal failure-associated liver disease is reversed with 6 months of intravenous fish oil. JPEN J Parenter Enteral Nutr. 2014 Aug;38(6):682-92. doi: 10.1177/0148607113495416. Epub 2013 Jul 26. | |
| 28521607 | Result | Calkins KL, DeBarber A, Steiner RD, Flores MJ, Grogan TR, Henning SM, Reyen L, Venick RS. Intravenous Fish Oil and Pediatric Intestinal Failure-Associated Liver Disease: Changes in Plasma Phytosterols, Cytokines, and Bile Acids and Erythrocyte Fatty Acids. JPEN J Parenter Enteral Nutr. 2018 Mar;42(3):633-641. doi: 10.1177/0148607117709196. Epub 2017 Dec 18. |
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There was no wash-out or run-in period.
Recruitment for this study began in May 2005. Patients were recruited from the inpatient and outpatient setting at the University of California, Los Angeles.
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| ID | Title | Description |
|---|---|---|
| FG000 | Omegaven | Omegaven, 0.5 g/kg/d IV x 2 days, then 1 g/kg/d IV for 24 weeks or until parenteral nutrition discontinuation, death or transplant, whichever comes first. Subjects are eligible to restart Omegaven should they re-satisfy inclusion/exclusion criteria. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
62 subjects were consented for the study. 3 subjects were withdrawn from the study prior to starting the intervention. Hence, 59 subjects started the intervention and baseline characteristics are provided for these 59 subjects.
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| ID | Title | Description |
|---|---|---|
| BG000 | Omegaven | 0.5 g/kg/d IV x 2 days, then 1 g/kg/d IV for 24 weeks or until parenteral nutrition discontinuation, death or transplant, whichever comes first. Subjects are eligible to restart Omegaven should they re-satisfy inclusion/exclusion criteria. Omegaven: 0.5 gm/kg/d intravenous every day for 2 days, then 1 gm/kg/d intravenous everyday |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Time to Reversal of Parenteral Nutrition Associated Cholestasis | weeks | Posted | Mean | Standard Deviation | weeks | 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) |
|
|
24 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Omegaven | 0.5 g/kg/d IV x 2 days, then 1 g/kg/d IV for 24 weeks or until parenteral nutrition discontinuation, death or transplant, whichever comes first. Subjects are eligible to restart Omegaven should they re-satisfy inclusion/exclusion criteria. Omegaven: 0.5 gm/kg/d intravenous every day for 2 days, then 1 gm/kg/d intravenous everyday |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Sepsis | Infections and infestations | Systematic Assessment | Bacteremia, Urosepsis, Fungemia, Viral sepsis - positive culture with symptoms and need for more than 5 days of antibiotics/antifungals |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypotension | Cardiac disorders | Systematic Assessment | Change in blood pressure requiring the use of pressor support |
early termination because intervention was FDA approved, single site study, prospective observational study, small sample size, change in clinical practice over time
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Kara L. Calkins | UCLA | 310-825-9330 | KCalkins@mednet.ucla.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 12, 2018 | Jul 1, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D002779 | Cholestasis |
| D006963 | Hyperphagia |
| ID | Term |
|---|---|
| D001649 | Bile Duct Diseases |
| D001660 | Biliary Tract Diseases |
| D004066 | Digestive System Diseases |
| D012817 | Signs and Symptoms, Digestive |
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| ID | Term |
|---|---|
| C568345 | fish oil triglycerides |
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| 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) |
| Time to Full Enteral Feeds | discontinuation of parenteral nutrition | 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) |
| Growth Z-scores | Weight Z-scores at the end of the study. Formula used: (weight at end of study-average weight of reference population)/standard deviation of weight of reference population. The Z-score indicates the number of standard deviations away from the mean. A weight Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. A weight Z-score </= -2 indicates an underweight or malnourished status, while a weight Z-score >/= 2 indicates an overweight or obese status. | 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) |
| Platelet Counts at the End of the Study - Risk of Bleeding | platelet counts at the end of the study | 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) |
| Number of Participants With Essential Fatty Acid Deficiency | triene:tetraene ratio less than 0.2 | 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) |
| Markers of Inflammation | Serum Cytokines - interleukin-8 | 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) |
| Markers of Sterol Metabolism | Serum Phytosterols - stigmasterol | 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) |
| Markers of Bile Acid Metabolism | Serum Bile acids - total chenodeoxycholic acid | 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) |
| Markers of Fatty Acid Metabolism | Erythrocyte fatty acid - Docosahexaenoic Acid | 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) |
| 30411372 | Result | Wang C, Venick RS, Shew SB, Dunn JCY, Reyen L, Gou R, Calkins KL. Long-Term Outcomes in Children With Intestinal Failure-Associated Liver Disease Treated With 6 Months of Intravenous Fish Oil Followed by Resumption of Intravenous Soybean Oil. JPEN J Parenter Enteral Nutr. 2019 Aug;43(6):708-716. doi: 10.1002/jpen.1463. Epub 2018 Nov 8. |
| 30900274 | Result | Ong ML, Venick RS, Shew SB, Dunn JCY, Reyen L, Grogan T, Calkins KL. Intravenous Fish Oil and Serum Fatty Acid Profiles in Pediatric Patients With Intestinal Failure-Associated Liver Disease. JPEN J Parenter Enteral Nutr. 2019 Aug;43(6):717-725. doi: 10.1002/jpen.1532. Epub 2019 Mar 22. |
| 32072161 | Derived | Calkins KL, Thamotharan S, Ghosh S, Dai Y, Devaskar SU. MicroRNA 122 Reflects Liver Injury in Children with Intestinal Failure-Associated Liver Disease Treated with Intravenous Fish Oil. J Nutr. 2020 May 1;150(5):1144-1150. doi: 10.1093/jn/nxaa001. |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | days |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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| Secondary | Death | expiration | Posted | Count of Participants | Participants | 24 weeks, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) |
|
|
|
| Secondary | Number of Participants Who Underwent a Transplant | includes isolated liver or multi-visceral transplant including liver graft | Posted | Count of Participants | Participants | 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) |
|
|
|
| Secondary | Time to Full Enteral Feeds | discontinuation of parenteral nutrition | Posted | Mean | Standard Deviation | weeks | 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) |
|
|
|
| Secondary | Growth Z-scores | Weight Z-scores at the end of the study. Formula used: (weight at end of study-average weight of reference population)/standard deviation of weight of reference population. The Z-score indicates the number of standard deviations away from the mean. A weight Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. A weight Z-score </= -2 indicates an underweight or malnourished status, while a weight Z-score >/= 2 indicates an overweight or obese status. | Posted | Mean | Standard Deviation | Z-score | 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) |
|
|
|
| Secondary | Platelet Counts at the End of the Study - Risk of Bleeding | platelet counts at the end of the study | Posted | Mean | Standard Deviation | x10^3 cells/mL | 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) |
|
|
|
| Secondary | Number of Participants With Essential Fatty Acid Deficiency | triene:tetraene ratio less than 0.2 | Posted | Count of Participants | Participants | 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) |
|
|
|
| Secondary | Markers of Inflammation | Serum Cytokines - interleukin-8 | Posted | Mean | Standard Deviation | pg/mL | 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) |
|
|
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| Secondary | Markers of Sterol Metabolism | Serum Phytosterols - stigmasterol | Posted | Mean | Standard Deviation | mg/dL | 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) |
|
|
|
| Secondary | Markers of Bile Acid Metabolism | Serum Bile acids - total chenodeoxycholic acid | Posted | Mean | Standard Deviation | umol/L | 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) |
|
|
|
| Secondary | Markers of Fatty Acid Metabolism | Erythrocyte fatty acid - Docosahexaenoic Acid | Posted | Mean | Standard Deviation | Percent of Sum of Fatty Acids | 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) |
|
|
|
| 4 |
| 59 |
| 35 |
| 59 |
| 53 |
| 59 |
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| Thrombocytopenia | Blood and lymphatic system disorders | Systematic Assessment | Platelet count less than 20,000K |
|
| Respiratory Distress | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Change in respiratory status requiring intubation |
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| Hypotension | Cardiac disorders | Systematic Assessment | Hypotension requiring pressor support. |
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| Increased Creatinine | Renal and urinary disorders | Systematic Assessment | Requiring need for dialysis. |
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| Bleeding | Blood and lymphatic system disorders | Systematic Assessment | Bleeding requiring product replacement or medical intervention (does not include pressure or specific medications) or surgical intervention. |
|
| Necrotizing Enterocolitis | Gastrointestinal disorders | Systematic Assessment | necrotizing enterocolitis (stage II or III). |
|
| Pneumonia | Infections and infestations | Systematic Assessment | Diagnosis by clinical team |
|
| Urinary Tract Infection | Infections and infestations | Systematic Assessment | Diagnosis by clinical team and positive urine culture and need for at least 5 days of antibiotics |
|
| Seizures | Nervous system disorders | Systematic Assessment | EEG or clinical diagnosis |
|
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| Respiratory Distress | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Change in respiratory status requiring intubation or other support. |
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| Hyponatremia | General disorders | Systematic Assessment | Serum sodium less than 130 |
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| Hypertriglyceridemia | General disorders | Systematic Assessment | Triglycerides more than 300 mg/dL |
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| Metabolic Acidosis | General disorders | Systematic Assessment | potential of hydrogen less than 7.2 and/or requiring medical intervention (volume support, sodium bicarbonate) |
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| Bowel Rejection | Gastrointestinal disorders | Systematic Assessment | Clinical and histological evidence of rejection as well as clinical diagnosis by medical team |
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| Acute Life Threatening Event | General disorders | Systematic Assessment | Diagnosis by clinical team |
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| Increased Creatinine | Renal and urinary disorders | Systematic Assessment |
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| Hypoglycemia | Endocrine disorders | Systematic Assessment | Serum glucose < 60 mg/dL |
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| Hyperglycemia | Endocrine disorders | Systematic Assessment | Serum glucose >200 mg/dL |
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| Thrombocytopenia | Blood and lymphatic system disorders | Systematic Assessment | Platelet count <100,000 cell/cu.mm |
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| Thrombocytosis | Blood and lymphatic system disorders | Systematic Assessment | Platelet count >500,000 cu.mm |
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| Leukopenia | Blood and lymphatic system disorders | Systematic Assessment | White blood cell count <5000 cells/cu.mm |
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| Increased International Normalized Ratio | Blood and lymphatic system disorders | Systematic Assessment | International Normalized Ratio >1.4 |
|
| Clinical Bleeding | Blood and lymphatic system disorders | Systematic Assessment |
|
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| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |